Abstract

Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin receptors (AdipoR) -1 and -2. Plasma adiponectin depletion is associated with type 2 diabetes, obesity and cardiovascular diseases. Adiponectin therapy however, is yet unavailable owing to its large size, complex multimerization and functional differences of the multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S, 3S)-(+)- 5,7, 3',4'- tetrahydroxydihydroflavonol (GTDF) as an orally active adiponectin mimetic. GTDF interacted with both AdipoRs, with a preference for AdipoR1. It induced adiponectin-associated signaling and enhanced glucose uptake and fatty acid oxidation in vitro, which were augmented or abolished by AdipoR1 overexpression or silencing respectively. GTDF improved metabolic health, characterized by elevated glucose-clearance, β-cell-survival, reduced steatohepatitis, browning of white adipose tissue and improved lipid profile in an AdipoR1-expressing but not an AdipoR1-depleted strain of diabetic mice. The discovery of GTDF as an adiponectin mimetic provides a promising therapeutic tool for the treatment of metabolic diseases.